Ashdin Publishing Journal of Drug and Alcohol Research ASHDIN Vol. 2 (2013), Article ID 235651, 11 pages publishing doi:10.4303/jdar/235651 Review Article ΔFosB: a Molecular Switch for Reward Eric J. Nestler Fishberg Department of Neuroscience and Friedman Brain Institute, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1065, New York, NY 10029, USA Address correspondence to Eric J. Nestler, [email protected] Received 2 November 2012; Revised 10 November 2012; Accepted 20 November 2012 Copyright © 2013 E. J. Nestler. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract ΔFosB is a member of the Fos family of transcription implicated in these models. Prominent among these tran- factors. While all other family members are induced rapidly but scription factors is ΔFosB, a member of the Fos family of Δ transiently in response to a host of acute stimuli, FosB is unique proteins. This review provides a progress report on ΔFosB, in that it accumulates in response to repeated stimulation due to its unusual protein stability. Such a prolonged induction of ΔFosB, within which appears to play a unique role in the addiction process, the brain’s reward regions, has been implicated in animal models of as a way to illustrate the types of experimental approaches drug addiction, with a wealth of evidence indicating that ΔFosB that have been used to investigate transcriptional mecha- promotes reward and motivation and serves as a key mechanism of nisms of addiction. drug sensitization and increased drug self-administration. This has Δ been validated in humans postmortem, with elevated FosB levels Δ seen in reward regions of the addicted brain. As a transcription 2 Induction of FosB in nucleus accumbens by drugs of factor, ΔFosB produces this behavioral phenotype by regulating abuse the expression of specific target genes. We are identifying such ΔFosB is encoded by the fosB gene (Figure 1) and shares transcriptional targets of ΔFosB by use of a candidate gene approach as well as by use of genome-wide methods. Recent work has analyzed homology with other Fos family transcription factors, which chromatin remodeling—changes in the posttranslational modifications include c-Fos, FosB, Fra1, and Fra2 [45]. These Fos family of histones and other nuclear proteins at drug-regulated genes— proteins heterodimerize with Jun family proteins (c-Jun, Δ to delineate the detailed molecular mechanisms by which FosB JunB, or JunD) to form active AP-1 (activator protein-1) regulates target gene expression in vivo to mediate drug-induced synaptic, neural, and behavioral plasticity. These studies of ΔFosB are transcription factors that bind to AP-1 sites (consensus providing new insight into the molecular basis of drug addiction, which sequence: TGAC/GTCA) present in the promoters of is defining a host of new targets for possible therapeutic development. certain genes to regulate their transcription. Fos family Keywords addiction; depression; resilience; chromatin remodeling; proteins are induced rapidly and transiently in specific brain epigenetics; nucleus accumbens; drug abuse regions after acute administration of many drugs of abuse (Figure 2) (e.g., [18,23,86]). These responses are seen 1 Introduction most prominently in nucleus accumbens (NAc) and dorsal The study of transcriptional mechanisms of addiction is striatum, which are important mediators of the rewarding based on the hypothesis that regulation of gene expression and locomotor actions of the drugs. All of these Fos family is one important mechanism by which chronic exposure to proteins, however, are highly unstable and return to basal a drug of abuse causes long-lasting changes in the brain that levels within hours of drug administration. underlie the behavioral abnormalities that define a state of Very different responses are seen after chronic adminis- addiction [49]. A corollary of this hypothesis is that drug- tration of drugs of abuse (Figure 2). Biochemically modified induced changes in synaptic transmission and in neuronal isoforms of ΔFosB (Mr 35–37 kD) accumulate within the excitability and morphology in particular brain regions, same brain regions after repeated drug exposure, whereas which have been implicated in addiction, are mediated in other Fos family members show desensitization (i.e., part via changes in gene expression. reduced induction compared with initial drug exposures) [8, Work over the past 20 years has provided increasing evi- 11,21]. Such accumulation of ΔFosB has been observed for dence for a role of gene regulation in drug addiction mod- virtually all drugs of abuse (Table 1) (e.g., [24,34,42,44, els, as several transcription factors—proteins that bind to 46,53,54,60]), although different drugs differ somewhat in specific responses elements in the promoter regions of tar- the relative degree of induction seen in NAc core vs. shell get genes and regulate those genes’ expression—have been and dorsal striatum [59]. At least for some drugs of abuse, 2 Journal of Drug and Alcohol Research Figure 1: Biochemical basis of ΔFosB’s unique stability. ΔFosB and FosB are encoded by the fosB gene. ΔFosB is generated by alternative splicing and lacks the C-terminal 101 amino acids present in FosB. Two mechanisms are known that account for ΔFosB’s stability. First, ΔFosB lacks two degron domains present in the C-terminus of full length FosB (and found in all other Fos family proteins as well). One of these degron domains targets FosB for ubiquitylation and degradation in the proteasome. The other degron domain targets FosB degradation by a ubiquitin- and proteasome-independent mechanism. Second, ΔFosB is phosphorylated by several protein kinases at its N-terminus which further stabilizes the protein. Table 1: Drugs of abuse known to induce ΔFosB in the NAc after chronic administration. Opiates1 Cocaine1 Amphetamine Methamphetamine Nicotine1 Figure 2: Scheme showing the gradual accumulation of Ethanol1 Δ Phencyclidine FosB versus the rapid and transient induction of other Cannabinoids Fos family proteins in response to drugs of abuse. Top: 1Induction reported for self-administered drug in addition to the autoradiogram illustrates the differential induction of investigator-administered drug. Drug induction of ΔFosB has been Fos family proteins in the NAc by acute stimulation (1–2 h demonstrated for most drugs in both rats and mice. There are no after a single cocaine exposure) versus chronic stimulation Δ reports of drugs of abuse that do not induce FosB in NAc. (1 day after repeated cocaine exposure). Bottom: upper graph shows that several waves of Fos family proteins induction of ΔFosB appears selective for the dynorphin- (comprised of c-Fos, FosB, ΔFosB [19, kD isoform], Fra1, containing subset of medium spiny neurons located in these Fra2) are induced in NAc and dorsal striatal neurons by brain regions, those neurons that predominantly express acute administration of a drug of abuse. Also induced are dopamine D1 receptors [32,44,46,53], although more work biochemically modified isoforms of ΔFosB (35–37 kD); is needed to establish this with certainty. Drug induction they are induced at low levels by acute drug administration, of ΔFosB in NAc has recently been demonstrated in but persist in brain for long periods due to their stability. humans [67]. The lower graph shows that with repeated (e.g., twice daily) The 35–37 kD isoforms of ΔFosB dimerize predomi- drug administration, each acute stimulus induces a low level nantly with JunD to form an active and long-lasting AP-1 of the stable ΔFosB isoforms. This is indicated by the lower complex within these brain regions [8,22]. However, recent set of overlapping lines, which indicate ΔFosB induced by in vitro evidence has indicated that ΔFosB can also form each acute stimulus. The result is a gradual increase in the homodimers with distinct physico-chemical properties total levels of ΔFosB with repeated stimuli during a course compared to ΔFosB:JunD heterodimers [25]. An important of chronic treatment. This is indicated by the increasing focus of current research is to determine whether such stepped line in the graph. Journal of the International Drug Abuse Research Society 3 Table 2: Behavioral phenotype upon ΔFosB induction (2) the phosphorylation of ΔFosB at its N-terminus by in dynorphin/D1-type medium spiny neurons of NAc and Ca2+/calmodulin-dependent protein kinase II (CaMKII) and dorsal striatum1. casein kinase 2 and perhaps by other protein kinases [7, Stimulus Phenotype 67,74,75]. The mechanism by which phosphorylation of Cocaine Increased locomotor responses to acute administration ΔFosB at Ser27 increases its stability remains unknown. Increased locomotor sensitization to repeated The stability of the ΔFosB isoforms provides a novel administration molecular mechanism by which drug-induced changes in Increased conditioned place preference at lower doses gene expression can persist despite relatively long periods of Increased acquisition of cocaine self-administration at Δ lower doses drug withdrawal. We have, therefore, proposed that FosB Increased brain stimulation reward functions as a sustained “molecular switch” that helps Increased incentive motivation in progressive ratio initiate and then maintain an addicted state [40,50,51]. procedure Morphine Increased conditioned place preference at lower drug 3Roleof ΔFosB in NAc in regulating